Treatment of mental disturbances by chemotherapeutic means



United States The present invention relates to a treatment of mental disturbances by chemotherapeutic means. More particularly, it relates to a new method of treating certain anxiety stages and similar mental tensions by chemical means and a composition dosage form.

Mental disorders comprising the milder forms such as anxieties, hallucinations, and hyperactivity, as well as the severe stages of manic depression and schizophrenia, are disturbances of the mind which have only recently been attacked :by chemical means. In the last few years, a number of new drugs have been introduced to relieve the tensions by which most of these disturbances are caused. These drugs, commonly called tranquillizers, are usually quite acceptable for certain types of disturbances, but in general, have very little efiect on the severely disturbed mental patient. Furthermore, such tranquilizers very often cause objectionable signs and symptoms in the patient such as depression, disinterest in the surroundings, retreat from reality, and Withdrawal from activity.

A new method has now been found which, like the tranquilizers, relieve anxiety stages and nervous disorders, but, in contrast to the tranquilizers, has a calming effect without causing mental depression. It reduces and in some cases eliminates the outward signs of hostility and paranoid tendencies evidenced by aggression, combativeness and belligerency and certain types of withdrawal and detachment engendered by hostility, without causing central nervous system depression or sedation, in mentally disturbed human subjects in Whom the aforementioned signs are evident. This new efiect is called a normalizing effect. The new treatment consists in administering to a mentally disturbed subject N-benzoylpiperidine in dosage form. The new method of treatment may be carried out with any dosage form, i.e., desirable results may be accomplished by oral, intravenous, intramuscular, intraperitoneal, or subcutaneous administration of the compound of the present invention. Obviously, in treatment of humans, the oral administration is preferred due to its simplicity, whereas in animal studies, administration by various injection routes is sometimes easier to control.

N-benzoylpiperidine may be pressed into tablet form or it may be processed in gelatin capsules. Tablets or capsules may include other non-toxic ingredients ordinarily used for such preparations, e.g., fillers, adjuvants, carriers, flavoring agent, coloring agents, etc. In case of tablets, any form of tablet coating may be selected, but a sub-coating may be desirable in certain instances. N-benzoylpiperidine may also be used for the various injection routes together with physiologically acceptable solvents, diluents, carriers, etc. Solution concentrations of about 125 mg./cc. are best suited, although higher concentrations are acceptable with the more powerful solvents. Lower concentrations are also useful where N-benzoylpiperidine is less soluble in the solvent chosen and the required dose is small.

The efiective dosage for treating mental tensions and anxiety with N-benzoylpiperidine varies, of course, with the degree of disturbance to be treated and the route of administration selected. In animals, the preferred amount to be administered by intraperitoneal injection is between about 125 and 550 mg./kg. The normal oral dosage range for adult humans is from about 300 mg. to 5.0 g. per day but a single dose of about 0.5-1.0 g. produces definite improvement. The definitive amount which is actually administered will be determined by the attending physician. He will be guided by the skills of his art in prescribing an amount sufficient to attain normalization of the subject. These amounts are very low in view of the extremely low toxicity of the N-benzoylpiperidine. The low toxicity is exemplified by the fact that by oral administration of 2.5 g. per kg. to rats, all test animals remain in good health. However, at much lower doses the normalizing elfect is apparent. In contrast to treatment involving other chemicals for relief of mental disturbances, no sedation, dizziness, impairment of motor function and coordination, or hypnosis is observed at effective dosage levels. Furthermore, the subjects so treated remain alert, have a general feeling of improvement, and show improved appetite and sleep.

The effect of the new treatment is that of calming with relief from axieties and hallucinations. The new treatment normalizes the severely disturbed subject and creates normal activity patterns for those subjects disturbed by hallucinations: the restlessness and hyperactivity of the patients are relieved, thus permitting integration into normal life or full therapeutic programs.

These effects can be observed in animals by a series of tests such as initially developing mental stress by modifying previously trained habit patterns and thereafter administering N-benzoylpiperidine. Thus, the strain is placed on a habit pattern and is increased to a point at which certain objective signs of disquietude or other physical imbalance can be observed and measured, and under such conditions the new treatment method may be tried and studied.

To better illustrate the foregoing disclosure, reference is made to the following examples which are not to be considered the only applications of the new method Example 1 A sterile, aqueous solution of N-benzoylpiperidine is injected intraperitoneally into a group of rats at doses of 50 and ing/kg. respectively. All test animals show marked and prolonged muscle relaxation with diminishing activity at the higher dose and hypersensitivity lasting for about two hours.

In a strain of extremely viscous rats, N-benzoylpiperidine is administered intraperitoneally daily for four days at doses of 100 mg./kg./day each. Complete elimination of the combative viciousness is observed which returns within 48 hours after the treatment.

Example 2 A group of rats is kept individually in activity measurement cages. These cages are constructed in such a manner that the animals movements produce oscillations which are registered on a counter. The normal count of a healthy control rat averages about 100 in a fiveminute period. After treating the rats with 5 mg./l g. of the hallucinogen N-rnethyl-3-piperidyl-diphenylglycolate, the animals become confused and hyperactive; their oscillator count for equivalent periods climbs from 100 to about 1000. The injection of the hallucinogen is followed, after five minutes, with the intraperitoneal administration of 100 ing/kg. (0.00053 mol./kg.) of N- benzoylpiperidine to show complete recovery of the artificially caused hyperactivity.

When the order of administration is reversed and the hallucinogen injection follows the N-benzoylpiperidine injection within five minutes, no change in activity and habit pattern of the test animal is observed, demonstrating the complete blocking action of the new treatment to the effect of the hallucinogen.

Example 3 An adult, human, male subject complaining of considerable anxiety and restlessness is given a single dose of 500 mg. of N-benzoylpiperidine in a gelatin capsule. Within two hours, the patient experiences a feeling of relaxation and reports not having felt this good in weeks, although the subject had been on standard tranquilizer treatment previously with Thorazine hydrochloride (chlorpromazine hydrochloride).

From the above examples, it will be seen that N- benzoylpiperidine has a typical tranquilizing eifect, exhibited by the calmness produced and the relief of anxiety stages and hallucinations. Furthermore, it also shows muscle-relaxing properties. This latter term relates to the pharmacological efifect on the central nervous system which reduces skeletal muscle tensions without affecting motor function and alertness. reduces muscle tension and counteracts hallucinogenic agents and the behavioral changes produced by such agents.

The action of N benzoylpiperidine on mental disturbances is quite surprising since, ordinarily, N-substituted piperidine derivatives have no tranquilizing effect, and if at all active, tend to be stimulating rather than tranquilizing compounds. 'The new results achieved are rendered more desirable because of the simplicity of the treatment, the ease of administration, and the ready availability of the compound.

This application is a continuation of my former application, S.-N. 5,648, filed February 1, 1960, now abandoned.

Others may practice the invention in any of the numerous ways which will be suggested by this disclosure to one skilled in the art. All such practice of the invention is considered to be a part thereof provided it falls within the scope of the appended claims.

I claim: 7

1. A method of reducing and in some cases eliminating the outward signs of hostility and paranoid tendencies,

N-benzoylpiperidine thus evidenced by aggression, combativeness and belligerency, and certain types of withdrawal and detachment engendered by hostility, without causing central nervous system depression or sedation, in mentally disturbed human subjects in whom the aforementioned signs are evident, comprising administering to said human subjects a composition containing from about 0.3 g. to about 1.5 g. of N-benzoylpiperidine and a non-toxic pharmaceutical carrier.

2. The method of claim 1 wherein said composition is administered to said human subjects at a rate of from 0.3 g. per day to 5.0 g. per day.

3. A composition for reducing and in some cases eliminating the outward signs of hostility and paranoid tendencies evidenced by aggression, combativeness and belligerency, and certain types of withdrawal and detachment engendered by hostility, without causing central nervous system depression or sedation, in mentally disturbed human subjects in whom the aforementioned signs are evident, comprising from about 0.3 g. to about 1.5 g. of N-benzoylpiperidine and a non-toxic pharmaceutical carrier.

References Cited in the file of this patent UNITED STATES PATENTS 2,648,685 Reppe Aug. 11, 1953 2,654,754 Bruce Oct. 6, 1953 7 OTHER REFERENCES Good-win: The Pharm. 1., vol. 181, September 27, 1958, pp. 233-235.

Drug Trade News, Mfg. Sec., vol. 33:18, September 8, 1958, p. 75. p i

' Modell: IAMA, vol. 167:18, pp. 2190-2l99, August 30, 1958..

Chem. Abst. (1), vol. 38, 1944, p. 2651 (2), vol 37, 1043, p. 3750 (3), vol. 49, 1055, p. 2567 (4), vol. 47, 1953, p. 1700 (5), vol. 47, 1953, p. 2703 

1. A METHOD OF REDUCING AND IN SOME CASES ELIMINATING THE OUTWARD SIGNS OF HOSITILITY AND PARANOID TENDENCIES EVIDENCED BY AGGRESSION, COMBATIVENESS AND BELLIGERENCY, AND CERTAIN TYPES OF WITHDRAWAL AND DETACHMENT ENGENDERED BY HOSTILITY, WITHOUT CAUSING CENTRAL NERVOUS SYSTEM DEPRESSION OR SEDATION, IN MENTALLY DISTURBED HUMAN SUBJECTS IN WHOM THE AFOREMENTIONED SIGNS ARE EVIDENT, COMPRISING ADMINISTERING TO SAID HUMAN SUBJECTS A COMPOSITION CONTAINING FROM ABOUT 0.3 G. TO ABOUT 1.5 G. OF N-BENZOYLPIPERIDINE AND A NON-TOXIC PHARMACEUTICAL CARRIER. 